Using a case series of 600 patients with melanoma, we will perform an integrated molecular epidemiologic study to correlate genetic susceptibility phenotype and genotype data from lymphocytes and to extend these findings in surrogate tissue to the tumor tissue. We will measure functional nucleotide excision repair (NER) capacity by using the host cell reactivation assay with plasmids damaged by ultraviolet light and determine the frequencies of polymorphisms in the DNA repair genes (ERCC1, XPA, XPB, XPC, XPD, XPF, and XPG) implicated in the NER pathway. We will correlate the genotypes with functional NER activity. We hypothesize that individuals with """"""""adverse"""""""" genotypes of the NER pathway will have poorer DNA repair capacity (DRC) than individuals with wild-type genotypes. In a subset of 400 patients, we will also determine the frequencies of mutations in the newly described BRAF gene and loss of heterozygosity (LOH) at lp36, 6q22-23, 8p22-24, 9p21-22, 10q23, and 1lq23 in tumor tissues and compare these tumor markers with sunlight exposure levels and constitutional markers of genomic instability (DRC and genotypes measured in lymphocytes). We hypothesize that the severity of mutations and loci-specific alterations in tumor tissues will be correlated with adverse susceptibility markers in surrogate tissue and with degree of exposure. The overarching goal of these studies is to determine whether the lymphocyte markers that we have already shown to be significant predictors of cancer risk (DRC and DNA repair gene polymorphisms) are an adequate reflection of genetic events in the target organ tissue. This finding will have substantial implications for future large-scale population-based molecular epidemiology studies and risk assessment for prevention and early detection of melanoma. Surrogate markers that best predict carcinogenic events in the target tissue will be useful for identifying high-risk subgroups for intensive screening and chemopreventive interventions. The ability to rapidly screen individuals for risk using minimally invasive procedures (blood analysis) has immense clinical implication.
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